The long-term objectives of this proposal "Long-Circulating Targeted Nanoparticles for Non-Hodgkin's Lymphoma Treatment" are to (1) develop a novel, surface-modified PLGA nanoparticle system for the targeted delivery of therapeutic compounds and (2) use this technology to improve doxorubicin safety and efficacy in non-Hodgkin's lymphoma treatment. Doxorubicin (adriamycin) is a proven effective chemotherapeutic agent used extensively in the treatment of lymphoma. Unfortunately, its clinical efficacy can be inadequate, and more than 20,000 NHL patients die each year, despite treatment. In addition, doxorubicin is limited by dose- dependent and cumulative toxicities, the most serious of these being irreversible cardiomyopathy and congestive heart failure. The controlled, sustained release of chemotherapeutics from biodegradable PLGA nanoparticles has been shown to be effective in increasing drug efficacy due to the ability to better deliver drug intracellularly and for extended periods of time. Carigent Therapeutics has developed a methodology for surface-modifying PLGA nanoparticles, enabling not only the addition of sufficient surface PEG groups to prevent clearance by the body, but also targeting moieties such as antibodies to improve the specificity and potency against lymphoma cells. Towards this goal, the proposal is structured into 3 specific aims: (1) the formulation and characterization of PLGA nanoparticles with the novel surface modification, (2) the in vitro optimization of nanoparticle surface composition of both shielding (PEG) and targeting (anti-CD19) moieties, and (3) the in vivo characterization of nanoparticle pharmacokinetics and distribution in a mouse model, and efficacy against a lymphoma model. The early portions (specific aims 1 and 2) of the project involve the in vitro characterization of the nanoparticle system; including activity and release of drug from nanoparticles in a simulated physiologic environment. In addition, the effect PEG surface shielding and antibody targeting ligands have on both nanoparticle uptake by macrophages (for clearance) and B-cell killing (for efficacy) will be evaluated. We believe these first two specific aims will lead to a doxorubicin nanoparticle design capable of circulating through the vascular system long enough to allow targeting ligands to direct the particle inside tumor cells. In specific aim 3, this optimized formulation will be tested in a mouse model of lymphoma to determine efficacy, safety, and pharmacokinetics in a small animal model. The proposal titled "Long Circulating Targeted Nanoparticles for Non-Hodgkin's Lymphoma Treatment" outlines the development of a tumor-targeting, biodegradable nanoparticle formulation of doxorubicin designed for use against lymphoma. This proposal presents a novel potential therapeutic for use in lymphoma treatment, but the technology can be more broadly applied towards the improvement of safety and efficacy of many chemotherapeutics in cancer treatment. [unreadable] [unreadable] [unreadable]